FDA Warnings Not Heeded Equally

Action Points

Reaction to FDA notices about drug risks is highly variable, with some notices having a wide impact and others garnering a delayed response or none at all.

Point out that warnings about potential serious adverse events with specific drugs were associated with large drops in use of those agents, but the impact varied by drug.

The attention paid to FDA notices about drug risks appears to be highly variable, with some notices having a wide impact and others garnering a delayed response or none at all, researchers found.

In a review of the literature, serious adverse event warnings appeared to be most heeded of all FDA communications, but response still varied depending on the drug, Caleb Alexander, MD, of the University of Chicago, and colleagues reported in Medical Care.

For instance, use of rosiglitazone (Avandia) fell tremendously after an FDA warning about cardiovascular events associated with use of the drug.

On the other hand, cautioning against the use of long-acting beta-agonists (LABAs) without inhaled controller medications didn't impact the use of those drugs in asthma, the researchers found.

"We will need a better understanding of how to make [FDA risk communications] work, and where they can go wrong," Alexander said in a statement. "And we will need more and better studies of the successes and failures of this process."

To assess the full impact of FDA risk communications on the use of drugs and other outcomes, the researchers looked at 49 studies, published between 1990 and 2010, that evaluated the success of these notices.

They divided the notices into four categories:

Warnings about serious adverse events

Recommendations against use in specific subpopulations

Prevention of drug-drug interactions

Calls for increased lab or clinical monitoring

Warnings about potential serious adverse events with specific drugs were associated with large drops in use of those agents, but the impact varied by drug, as seen with rosiglitazone versus LABAs, the researchers found.

Notices about use of drugs for certain populations tended to spill over into others, they reported. For instance, a warning about antidepressant use in children and adolescents led to declines in their use among adults as well.

"As with other public policies, FDA communications have the potential for unintended consequences," they wrote.

They also found that warnings about drug-drug interactions appeared to take a long time to be put into practice. Several studies found the largest declines in cisapride (Propulsid) co-prescribing happened only after a third FDA warning, and the greatest drop in terfenadine (Seldane) co-prescribing didn't occur until 18 months after the initial notice.

Finally, there was no evidence that practitioners heeded recommendations about increased monitoring, though some may have done so transiently, Alexander and colleagues found.

Rates of glucose testing for patients on antipsychotics, for example, went unchanged after the FDA advised keeping watch for hyperlipidemia and diabetes, while rates of liver enzyme monitoring after a black box warning for troglitazone (Rezulin) increased slightly after FDA warnings, but waned again over time.

Studies that assessed provider attitudes about FDA communications generally found high levels of clinician awareness of warnings and label changes.

The researchers concluded that based on settings where incident and prevalent use were examined, notices are adopted more quickly for new patients rather than those continuing on their medication.

They also said the findings suggest that "warnings will be most effective in cases where they are specific, where acceptable alternatives are available, and where the messaging is reinforced over time."

They called for more research on factors associated with fast and sustained responses to risk communications, and continued work on characterizing the effects of advisories and warnings on a variety of behaviors "to enhance the science of risk communication regarding prescription drugs."

The study was limited by the heterogeneity of the included analyses and because regulatory advisories have a level of complexity that may not be fully captured by the studies.

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